Seroepidemiologic data as well as molecular analysis firmly establishes the association between the human retrovirus human T cell leukemia virus type-I (HTLV-I) and the diseases adult T cell leukemia/lymphoma (ATL) and HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In contrast to human immunodeficiency virus type-I (HIV-1) infection where the majority of those infected develop disease, only a small percentage of those infected with HTLV-I will develop ATL. Because of the inability to detect virus expression by standard ribonucleic acid (RNA) and protein analyses in patients, the exact role the virus plays in disease pathogenesis remains unclear. Newer methodologies have allowed the reexamination of the role of the virus in pathogenesis. Reverse transcriptase-polymerase chain reaction amplification of specific HTLV-I cDNAs resulted in the mapping of at least three new cDNAs, one of which is a candidate for the monocistronic expression of an HTLV-I protein, p2l rex, of unknown function and two contain potential open reading frames for new proteins. When RNA from peripheral blood lymphocytes of HTLV-I infected patients were examined by similar methods, virus expression was detected in the majority of samples analyzed. To further support the role of continued virus expression in disease pathogenesis, recombinant Tax protein could be taken up by noninfected lymphocytes and results in increased proliferation of cells of lymphoid and glial origin. A number of cofactors may play a role in HTLV-I-associated disease pathogenesis. Specific viral proteins from the herpesvirus, cytomegalovirus, significantly down regulates the expression from the HTLV-I promoter. Viral expression and, specifically, expression of Tax protein enhances the expression of tumor necrosis factor beta in vitro and this cytokine may result in some of the pathologic effects such as severe hypercalcemia associated with ATL. Understanding the control of viral expression in vivo during diseases will give insight into novel approaches for therapy.